Evidence indicates that many localized bacterial infections are due to bacteria adhering to epithelial cells by means of bacterial fibrillar structures known as fimbriae, fibrillae or pili. (S. Hultgren et al., PCT Publication WO 9514028, published May 26, 1995). The fimbriae are filamentous assemblies of protein subunits composed of lectins that bind to specific sugar-containing receptors on the host cells. The fimbriae are classified according to the sugar-specificity exhibited when they attach to cell receptors. Type 1 fimbriae, which exhibit mannose-specific binding, are the most common type. Some other types of fimbriae and their sugar specificities are: type 2, Gal.beta.4Glc; type P, Gal.alpha.4Gal; type G, N-Acetylglucosamine; type S, NeuAc.alpha.2.fwdarw.3Gal.beta.GalNAc; type K99, NeuGc.alpha.2.fwdarw.3Gal.beta.4Glc; as well as galactose-specific, L-fucose-specific, N-Acetylglucosamine-specific, Gal.beta.4GlcNAc-specific, and GlcNAc.beta.3Gal-specific fimbriae. (N. Sharon (1987) FEBS Letters 217: 145-157).
Enterobacteria that express Type 1 fimbriae include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Serratia marcescens, Shigella flexneri (N. Sharon (1987) supra), and Citrobacter, Morganella and Aeromonas spp. (H.-G. Leusch et al. (1991) Infection and Immunity 59: 2051-2057).
Bacteria that have type 1 pili can be identified by the fact that the type 1 pili agglutinate yeast cells and the agglutination is inhibited by D-mannose and .alpha.-D-mannosides. For example, the compound, 4-methylumbelliferyl .alpha.-mannoside, inhibits binding; it is 10-fold more effective than p-nitrophenyl .alpha.-D-mannoside in inhibiting yeast aggregation caused by E. coli but only 4-fold more effective than p-nitrophenyl .alpha.-D-mannoside in inhibiting yeast aggregation caused by K. pneumoniae. (B. Madison et al. (1994) Infection and Immunity 62:843-848).
Aromatic .alpha.-glycosides of mannose inhibit both the bacteria-induced agglutination of mannan-containing yeasts and the adherence of the bacteria to epithelial cells. The mannosides 4-methylumbelliferyl (.alpha.-mannoside and p-nitro-o-chlorophenyl .alpha.-mannoside are strong inhibitors. (N. Firon et al. (1987) Infection and Immunity 55(2):472-476; N. Sharon (1987) supra).
E. coli and Salmonella bind to glycoproteins of the family of carcinoembryonic antigens (CEA), to nonspecific cross-reacting antigen (NCA-55) and to biliary glycoprotein (BGP-85). There is binding inhibition of E. coli (but not of salmonellae) to CEA and NCA-55 when the inhibitors, 4-methylumbelliferyl-.alpha.-mannoside, p-ethoxyphenyl-.alpha.-mannoside and p-methoxyphenyl-.alpha.-mannoside are introduced. (H.-G. Leusch et al. (1991) supra).
Other compositions and compounds that bind to type 1 fimbriae are oligosaccharides that are treated with enzyme to leave alpha 1-2 bonds between mannose residues. These active compounds are glycopeptides and/or oligosaccharides. U.S. Pat. No. 5,198,352 to Neeser et al.
While the above-named inhibitors are known, what is needed is more effective inhibitors that can be used clinically. Such an inhibitor should exhibit increased binding to fimbriae or compete more effectively with the receptor and should be readily synthesized.